FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Olmesartan medoxomil of formula I.

BACKGROUND OF THE INVENTION

Olmesartan medoxomil is chemically known as 4-(l-hydroxy-l-methylethyl)-2-propyl-1-[[2'-(l#-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]-methyl]-l#-imidazole-5-carboxy!ic acid, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester. Olmesartan medoxomil is an ATj-subtype angiotensin II receptor antagonist. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Olmesartan medoxomil blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT] receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. Olmesartan medoxomil is used for the treatment of hypertension and is marketed under the brand name Benicar®.

Olmesartan and its pharmaceutically acceptable esters and salts are disclosed in US 5,616,599.

US '599 also discloses a process for the preparation of Olmesartan medoxomil (I), by condensing 4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (II) with 5-[4'-(bromomethyl)[l,l'-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (III) in the presence of sodium hydride and N,N-dimethylformamide, followed by isolation using column chromatography to produce trityl Olmesartan ethyl ester (IV), which is further treating with lithium hydroxide monohydrate in the presence of dioxane to produce lithium salt of trityl Olmesartan (IVa). Lithium salt (IVa) is reacted with 4-chloromethyl-5-methyl-l,3-dioxol-2-one (V) in the presence of potassium carbonate and N,N-dimethylacetamide to produce trityl Olmesartan medoxomil (VI), which is de-tritylated in the presence of aqueous acetic acid to produce Olmesartan medoxomil (I). The process is as shown in Scheme-I below:

The major disadvantage with the above process is that the formation of undesired impurities during the condensation of 4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (II) with 5-[4'-(bromomethyl)[l,r-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (III). Column chromatography is used to remove the impurities. Employing column chromatography technique is tedious and laborious and also involves use of large quantities of solvents, and hence is not suitable for industrial scale operations.

WO 2007/047838 A2 discloses a process for the preparation of Olmesartan (I) by condensing dimethyl-2-propylimidazole-4,5-dicarboxylate (VII) with 5-[4'-(bromomethyl)[l,r-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (III) in the presence of an alkali base and solvent to produce dimethyl 2-propyl-l-[4-[2-(trityltetrazol-5-yl)phenyl]methylimidazole-4,5-dicarboxylate (VIII), which is further reacted with Grignard reagent in the presence of a solvent to produce trityl Olmesartan methyl ester (IX), followed by reaction with alkaline base in the presence of ketone solvent to produce trityl Olmesartan (X). Compound (X) is reacted with 4-chloromethyl-5-methyl-l,3-dioxol-2-one (V) in the presence of phase transfer catalyst and alkali base and solvent to produce trityl Olmesartan medoxomil (VI), which is de-tritylated in the presence of aqueous acid to produce Olmesartan medoxomil (I). The process is as shown in Scheme-II below:

It has now been found that, during the condensation of 5-[4'-(bromomethyl)[l,r-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (III) with 4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (II) or dimethyl-2-propylimidazole-4,5-dicarboxilate (VII), the 5-[4'-(bromomethyl)[l,1'-biphenyl]2-yl]-N-(triphenylmethyl) tetrazole (III) and dibromomethyl biphenyl trityl tetrazole (IIIa) remained unreacted up to 1% as impurities. Removal of these impurities found necessary as these impurities are genotoxic and limit of these impurities together is NMT 37.5 ppm in Olmesartan medoxomil drug substance. Further, compounds of formulae (III) & (IIIa) are carried forward in subsequent reaction steps and resulted in Olmesartan (I) with the undesired impurity Olmesartan methyl biphenyl tetrazole ester of formula (XI), which is difficult to remove and required repeated purification steps. This results in poor yield and quality of the Olmesartan product.

Hence, there is a need to develop a process, which provides isolation of trityl Olmesartan methyl ester (IX), which is substantially free from impurities (III) & (IIIa) without column chromatography, to obtain pure trityl Olmesartan methyl ester (IX).

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Olmesartan medoxomil (I) of high purity on commercial scale.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a process for the purification of trityl

Olmesartan methyl ester of formula (IX), which comprises, crystallizing the crude compound (IX) from a solvent to produce pure compound (IX) substantially free of impurities (III) & (IIIa).

In another embodiment, the present invention provides a process for the preparation of trityl Olmesartan methyl ester (IX), which comprises, (i) condensing methyl 4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylate of formula (XII), with 5-[4'-(bromomethyl)[ 1,1 '-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole of formula (III), to produce a reaction mixture containing trityl Olmesartan methyl ester of formula (IX), (ii) treating the reaction mixture containing trityl Olmesartan methyl ester (IX) with a solvent to isolate trityl Olmesartan methyl ester of formula (IX).

In another embodiment, the present invention also provides a process for the conversion of trityl Olmesartan methyl ester (IX) as such or in purified form to Olmesartan medoxomil (I).

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention relates to a process for the preparation of pure trityl Olmesartan methyl ester (IX).

The process comprises, condensation of methyl 4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate (XII) with 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III) to produce trityl Olmesartan methyl ester (IX).The reaction is carried out in the presence of a base in a solvent.
The base used is selected from an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like; organic base such as diethylamine, triethylamine, tert-butylamine, diisopropylamine, and the like. The solvent used in the above reaction is selected from N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, acetone, toluene, ethyl acetate or mixtures thereof. The condensation reaction is carried out at a temperature of about 30-100°C for a period of about 30min to 40 hours.

After completion of the reaction, a solvent selected from acetone, ethyl acetate, water, acetonitrile or mixtures thereof is added and cooled the reaction mass to 0 to 10°C, followed by stirring for 30min to 2 hrs. Filtered the slurry containing trityl Olmesartan methyl ester (IX), followed by washing with water.

Crude trityl Olmesartan methyl ester (IX) is suspended in a solvent selected from toluene, xylene, ethyl acetate, methylene chloride, ethylene chloride, chloroform, acetone, acetonitrile, methyl isobutyl ketone. Separate the bottom aqueous layer and cool the organic layer to 40-45°C and continue stirring at 40-45°C, optionally in the presence of a co-solvent. Thereafter, cool the resulting slurry to 0 to -5°C and continue stirring at this temperature for lh. The precipitated pure trityl Olmesartan methyl ester is filtered at 0 to -5°C and washed with a solvent selected form diisopropyl ether, diethyl ether, methyl tertiary butyl ether, cyclohexane or mixtures thereof. The product is dried at 70-80°C under reduced pressure (~10 mmHg) until constant weight obtained.
In another embodiment, the present invention relates to a process for the preparation of Olmesartan medoxomil of formula (I).

The process comprising, pure trityl Olmesartan methyl ester (IX) obtained by the above process is treated with a base in a solvent to produce corresponding salt of trityl Olmesartan (IVd).The base used in the above reaction is selected from an alkali metal hydroxide selected from sodium hydroxide, lithium hydroxide, cesium hydroxide etc. The solvent used in the above reaction is selected from tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, water, ethylene glycol or mixtures thereof. The reaction is carried out at a temperature of about 15-100°C.

After completion of the reaction, reaction mixture is concentrated to produce salt of trityl Olmesartan (IVd) as a residue, which is used as such in the next reaction. Alternatively, residue containing salt of trityl Olmesartan (IVd) is dissolved in a organic solvent selected from ethyl acetate, butyl acetate, methyl acetate, methylene chloride, ethylene chloride or mixtures thereof. The resulting solution is washed with sodium chloride solution, followed by removing the organic solvent to produce a salt of trityl Olmesartan

(IVd), which is optionally crystallized from solvent selected from acetonitrile, acetone, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof.

Reacting the salt of trityl Olmesartan (IVd) with 4-halomethyl-5-methyl-l,3-dioxol-2-one (Va), wherein the halo represents CI, Br, F & I, in the presence of an alkali halide in a solvent to produce trityl Olmesartan medoxomil (VI).

The solvent used in the above reaction is selected from tetrahydrofuran, N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, ethyl acetate, toluene, acetone, methanol, ethanol, isopropanol, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof. The alkali halide is selected from sodium chloride, sodium bromide, sodium iodide, lithium chloride, cesium chloride or mixtures thereof.

This reaction is optionally carried out in the presence of a phase transfer catalyst (PTC), selected from tetraethylammonium-p-toluenesulfonate, tetrapropylammonium trifluoromethane sulfonate, tetraphenylphosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenylphosponium chloride, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyltriphenylphosphonium iodide, phenyltrimethylammonium chloride, tetrabutylammonium hydroxide, tetrabutylammonium perchlorate, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctylammonium bromide, tetraphenylphosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylraethylammonium chloride, wherein tetrabutylammonium salts and particularly tetrabutylammonium halides, e.g. the bromides are especially preferred. The reaction is carried out at a temperature of about 15-40°C, for a period of about 1 to 5 hrs.

After completion the reaction, solvent selected from ethyl acetate, butyl acetate, methyl acetate, toluene, xylenes, methylene chloride, ethylene chloride or mixtures thereof and water is added to the reaction mass and separated the layers. Organic layer is concentrated to remove the solvent to 1/3 volume and second solvent selected from diisopropyl ether, acetonitrile, hexanes, diethyl ether or mixtures thereof; is added to the concentrated mass containing trityl Olmesartan medoxomil (VI). Filtered the resulting solid and dried under reduced pressure. Alternatively, organic layer containing trityl Olmesartan medoxomil (VI) is completely concentrated to residue and used as such in the de-tritylation step.

Trityl Olmesartan medoxomil (VI) is detritylated in the presence of an aqueous acid to produce Olmesartan medoxomil (I).

The acid used in the de-tritylation reaction is selected from carboxylic acids such as formic acid, acetic acid, oxalic acid; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid; inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid or mixtures thereof.

The reaction is carried out at a temperature of about 10 to 100°C, for a period of about 30 min to 5 hrs. After completion of the reaction, the reaction mixture is filtered to remove the by-product, i.e trityl alcohol through hyflo. The filtrate containing Olmesartan medoxomil (I) is diluted with water and extracted with an organic solvent selected from methylene chloride, ethylene chloride, ethyl acetate, butyl acetate, methyl acetate, toluene, xylenes or mixtures thereof. The organic layer is diluted with water and adjusted the pH to 7.0 to 7.5 using a base selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, pyridine, alkyl amine etc. Organic layer is separated and partially concentrated under reduced pressure under heating. The resulting concentrated mass containing Olmesartan medoxomil (I) is stirred with a solvent selected from acetonitrile, THF, acetone, methanol, ethanol, isopropanol, ethyl acetate or mixtures thereof, and filtered to produce crude Olmesartan medoxomil (I).

Olmesartan medoxomil (I) crude obtained by the above process is purified by known methods, for example recrystallization by dissolving in a solvent selected from methanol, ethanol, isopropanol, methylene chloride, tetrahydrofuran, acetone, acetonitrile, ethyl acetate or mixtures thereof; preferably in acetone/ethyl acetate mixture, and precipitating pure Olmesartan medoxomil (I) by cooling the solution to about 0-3 0°C, or by adding an anti solvent selected from cyclohexane, n-hexane, heptane, diisopropyl ether, etc.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE:

Stage I:

Preparation of trityl Olmesartan methyl ester

Powdered potassium carbonate (114.50g) followed by 5-[4'-(bromomethyl)[l,l'-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (362.30 g) were added to a solution of 4-(l-Hdroxy-1-methylethyl) 2-propylimidazole-5- carboxylic acid, methyl ester (150 g) in N,N-dimethylacetamide (750 ml) at 25-30°C. The temperature of the reaction mass was raised to 40-45 °C and stirring was continued at this temperature till completion of the reaction. Thereafter, acetone (1.05 Lt) was add to the reaction mass at 40-45°C and the slurry was cooled to 20-25°C. DM water (510 ml) was added at 20-25°C, cooled to 2-5°C and stirred for 1 h. The product (trityl Olmesartan methyl ester) was filtered and washed with DM water (3 Lt, 25-30°C). Trityl Olmesartan methyl ester crude was suspended (~lkg, wet) in a pre-heated toluene (600 ml, 70-80°C) at 70-80°C and the contents were stirred at this temperature to obtain a clear solution. The bottom aqueous layer was separated and the organic layer was cooled to 40-45°C and stirring was continued at the same temperature for 1 h. Thereafter, the resulting slurry was cooled to 0 to -5°C and stirring was continued at this temperature for lh. The product was filtered at 0 to -5°C and washed with diisopropyl ether (300 ml). The product was dried at 70-80°C under reduced pressure (-10 mmHg) until constant weight obtained to afford trityl

Olmesartan methyl ester as white crystalline powder (365g) having greater than 98% of HPLC purity.

Stage II:

Preparation of trityl Olmesartan medoxomil

Trityl Olmesartan methyl ester (350 g) was dissolved in tetrahydrofuran (2.10 Lt) at 25-30°C and methanol (350 ml) followed by a pre-cooled solution of sodium hydroxide (-100 ml, prepared by dissolving 21 g of sodium hydroxide in 87.50 ml of DM water, 10-15°C) were added at 20-30°C. Thereafter, the contents were stirred at 25-30°C till completion of the reaction. The reaction mass was concentrated under reduced pressure (200-20 mm Hg) and the temperature was maintained below 35°C till no more solvent distils to obtain trityl Olmesartan sodium salt as viscous mass. The trityl Olmesartan sodium salt was dissolved in JV,JV-dimethylacetamide (1050 ml) at 30-35°C. 4-chloromethyl-5-methyl-l,3-dioxol-2-one {Medoxomil chloride, 83.52 g, 90% purity, by GC) followed by sodium iodide (10.50 g) were added to the reaction mixture at 30-35°C. The reaction mixture was stirred at 30-35°C till completion of the reaction, then the reaction mass was diluted with ethyl acetate (3.50 Lt) and DM water (3.50 Lt) followed by sodium metabisulphite (3.50 g) were added and stirring was continued at this temperature for 15 min. The organic layers were separated and washed the above organic layer with -20% w/w aqueous sodium chloride (2 x 1750 ml). Finally, the organic layer was washed with DM water (175 ml) at 30-35°C and concentrated under reduced pressure (400-300 mm Hg) at 35-42°C to distil -2.0 Lt of ethyl acetate. Diisopropyl ether (1.75 Lt) was added to the concentrated mass at 35-40°C and stirred the contents for 15 min. The slurry was cooled to 0-5°C and stirring was continued at this temperature for 30 5 min. The product was filtered and washed it with 1:1 v/v mixture of ethyl acetate and diisopropyl ether (700 ml). The product was dried at 50-55°C under reduced pressure until constant weight obtained to afford trityl Olmesartan medoxomil (371 g) as white powder having greater than 99.5% of HPLC purity.

Stage III:

Preparation of Olmesartan medoxomil

Trityl Olmesartan medoxomil (300 g) was suspended in 75% v/v acetic acid in water (1.50 Lt) at 25-30°C and the contents were stirred at 25-30°C till completion of the reaction. Thereafter, trityl alcohol by-product was filtered through hyflo and the residue was washed with 75% v/v acetic acid in water (300 ml, 25-30°C). Methylene chloride (2.10 Lt) followed by DM water (1.50 Lt) were added to the filtrate and the contents were stirred at this temperature for 15 min. The organic extract was washed with DM water (2 x 3 Lt) at 20-30°C. The organic layer was mixed with DM water (300 ml) and the pH was adjusted to 6.5-7.0 at 20-30°C with aqueous sodium bicarbonate solution. Thereafter, the organic layer (~2.6 Lt) was separated at 20-30°C and concentrated at ambient pressure till the mass temperature reaches 46-50°C. Acetone (1.20 Lt) was added to the concentrated mass at 45-50°C. Distillation was continued at 50-60°C at ambient pressure to collect ~1.0 Lt of distillate. The resulting suspension was cooled to 0-5°C and stirring was continued at the same temperature for 1 h. Olmesartan medoxomil was filtered at 0-5°C and washed with pre-cooled acetone (150 ml, 0-5°C). Olmesartan medoxomil-crude (wet mass, -175 g) was suspended along with carbon enoanticromos (6 g) in acetone (2.97 Lt) at 20-30°C. The suspension was heated to reflux at 53-56°C and stirring was continued at the same temperature for 30 min to dissolve Olmesartan medoxomil. The contents were cooled to 45-50°C. Carbon was removed through hyflo at 45-50°C and the residue was washed with preheated acetone (350 ml, 45-50°C). Ethyl acetate (175 ml) was added to the filtrate at 30-40°C. The solution was concentrated to a volume of-500 ml at 50-60°C at ambient pressure. The concentrated slurry was cooled to 0-5°C stirred for 30 min. The product was filtered at 0-5°C and washed with pre-cooled ethyl acetate (175 ml, 0-5°C). The product was dried at 50-55°C under reduced pressure (-10 mm Hg) till constant weight obtained to afford Olmesartan medoxomil as white crystalline powder (153 g) having greater than 99.8% of HPLC purity.

Stage IV:

Purification of crude Olmesartan medoxomil

Method A:

Olmesartan Medoxomil crude (25g) was dissolved in acetone (375 ml) at reflux temperature, carbon (1.25 g) was added and stirring was continued for 30 min at this temperature. The contents were cooled to 45-50°C and the carbon was filtered through hyflo. The residue was washed with hot acetone (25 ml). Ethyl acetate (50 ml) was added to the filtrate and concentrated at ambient pressure to a volume of 90 ml. Thereafter, the resulting crystals were cooled to 0-5°C and stirred for 30 min at this temperature. The product was filtered, washed with ethyl acetate and dried to afford Olmesartan Medoxomil (22.5 g) as white crystalline powder having >99.9% of HPLC purity.

Method B:

Olmesartan Medoxomil crude (25g) was dissolved in acetone (375 ml) at reflux temperature, carbon (1.25 g) was added and stirring was continued for 30 min at this temperature. The contents were cooled to 45-50°C and the carbon was filtered through hyflo. The residue was washed with hot acetone (50 ml). Methylene chloride (25 ml) was added to the filtrate and concentrated to a volume of 90 ml at ambient pressure. Thereafter, the resulting crystals were cooled to 0-5°C and stirred for 30 min at this temperature. The product was filtered, washed with ethyl acetate and dried to afford Olmesartan Medoxomil (22.5 g) as white crystalline powder having >99.9% of HPLC purity.

We Claim

1. A process for the purification trityl Olmesartan methyl ester of formula (IX), which comprises, crystallizing the crude compound (IX) to produce pure compound (IX) substantially free of impurities (III) & (Ilia).

2. The process according to claim 1, wherein, the crystallization process comprises:

a) suspending the crude compound (IX) in a solvent under suitable temperature;
b) cooling the reaction mixture;
c) isolating the compound (IX).

3. The process according to claims 1 or 2, wherein, the crystallization is carried out by using a solvent selected from toluene, xylene, ethyl acetate, methylene chloride, ethylene chloride, chloroform, acetone, acetonitrile, methyl isobutyl ketone or mixtures thereof.

4. A process for the preparation of trityl Olmesartan methyl ester of formula (IX), which comprises,

(i) condensing methyl 4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylate of formula (XII), with 5-[4'-(bromomethyl)[ 1,1 '-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole of formula (III), to produce a reaction mixture containing trityl Olmesartan methyl ester of formula (IX); (ii) treating the reaction mixture containing trityl Olmesartan methyl ester with a solvent to isolate the compound (IX).

5. The process according to claim 4, wherein, the condensation in step-(i) is carried out by using a base in a solvent.

6. The process according to claim 5, wherein, the base is selected from an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like; organic base such as diethylamine, triethylamine, tert-butylamine, diisopropylamine, and the like.

7. The process according to claim 5, wherein, the solvent is selected from N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, acetone, toluene, ethyl acetate or mixtures thereof.

8. The process according to claim 4, wherein the solvent used in the step-(ii) is selected from acetone, ethyl acetate, water, acetonitrile or mixtures thereof.

9. The process according to claim 1 or 2, further comprising conversion of trityl Olmesartan methyl ester (IX) to Olmesartan medoxomil (I).